Bottom Line:
Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming.The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells.In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses.

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACTAllergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.

Mentions:
We have previously shown that sensitization of mice by exposure to inhaled OVA leads to robust pulmonary Th2 responses (8). To test the role of LPS in these responses, we sensitized mice by intranasal exposure to OVA depleted of contaminating LPS (<0.001 μg) or OVA with a high (100 μg) or low (0.1 μg) dose of LPS. These low and high doses of LPS are analogous to reported endotoxin levels of samples from homes of atopic versus nonatopic children, respectively (5). Mice exposed to LPS-depleted OVA showed no airway inflammatory responses after challenge with inhaled antigen (Fig. 1 A) and had total BAL cell numbers equivalent to PBS controls. In contrast, mice sensitized with OVA containing low dose LPS demonstrated significant increases in total BAL cell numbers as well as lung tissue infiltrates and airway mucus secretion (Fig. 1, A and B). Both airway and tissue infiltrates were dominated by eosinophils, consistent with Th2-mediated inflammation. Draining lymph node (DLN) IL-5 and IL-13 production confirmed the Th2 nature of the inflammatory response (Fig. 1 C). Mice exposed to PBS or low dose LPS alone did not generate pulmonary inflammation after OVA challenge (Fig. 2 A).

Mentions:
We have previously shown that sensitization of mice by exposure to inhaled OVA leads to robust pulmonary Th2 responses (8). To test the role of LPS in these responses, we sensitized mice by intranasal exposure to OVA depleted of contaminating LPS (<0.001 μg) or OVA with a high (100 μg) or low (0.1 μg) dose of LPS. These low and high doses of LPS are analogous to reported endotoxin levels of samples from homes of atopic versus nonatopic children, respectively (5). Mice exposed to LPS-depleted OVA showed no airway inflammatory responses after challenge with inhaled antigen (Fig. 1 A) and had total BAL cell numbers equivalent to PBS controls. In contrast, mice sensitized with OVA containing low dose LPS demonstrated significant increases in total BAL cell numbers as well as lung tissue infiltrates and airway mucus secretion (Fig. 1, A and B). Both airway and tissue infiltrates were dominated by eosinophils, consistent with Th2-mediated inflammation. Draining lymph node (DLN) IL-5 and IL-13 production confirmed the Th2 nature of the inflammatory response (Fig. 1 C). Mice exposed to PBS or low dose LPS alone did not generate pulmonary inflammation after OVA challenge (Fig. 2 A).

Bottom Line:
Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming.The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells.In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses.

Affiliation:
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACTAllergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.